1-(indolyglyoxalyl)-piperidines



United States Patent 3,217,011 l-(ETDOLYLGLYOXALYD-PIPERIDINES BernardL. Zenitz, Colonic, N. assignor to Sterling Drug Inc., New York, N.Y., acorporation of Delaware N0 Drawing. Filed May 7, 1965, Ser. No. 454,186Claims. (Cl. 260-2943) This application is a continuation-in-part of myprior application S.N. 119,805, filed June 27, 1961, now U.S. Patent3,183,235, patented May 11, 1965.

This invention relates to l-[(3-indolyl)-lower-alkyl]- piperidines, 1-[(3-indolyl)-lower-alkyl]-loWer-alkylatedpiperidines, 1- (2-indolyl-lower-alkyl] -piperidines, 1- 2- indolyl -lower-alkyl]-lower-alkylated-piperidines, 1-[ lindolyl) lower-alkyl]-piperidines,l-[(l-indolyl)-loweralkyl]-loWer-alkylated-piperidines, theiracid-addition and quaternary ammonium salts, and to intermediates andprocesses for the preparation thereof.

The present invention resides in the concept of attaching to the l-, 2-,or 3-position of indole through an unsubstituted lower-alkylene bridgeinterposing from two to six carbon atoms, a l-(piperidyl) group or al-(loweralkylated-piperidyl) group further substituted in the piperidinering by substituents of a nature to be more fully described hereinafter.

The structural embodiments of the invention are represented by theformulas Where any one of the three free valences on the indole ring istaken up by the l-[lower-alkynpiperidine group i and the valences at the1- and 2-positions when not taken 3,217,011 Patented Nov. 9, 1965monocarbocyclic aryl; R represents hydrogen or from one to fivelower-alkyl radicals; R represents a member of the group consisting ofhydroxy, hydroxy-lower-alkyl, lower-alkanoyloxy, monocarbocyclicaroyloxy, lower-alkanoyloxy-lower-alkyl, monocarbocyclicaroyloxy-loweralkyl, cycloalkyl-lower-alkyl, carbo-lower-alkoxy,unsubstituted-carbamyl, N-lower-alkylcarbamyl, N-lower-akenyl carbamyl,N,N-di-lower-alkenylcarbamyl, aminocarbamyl (hydrazido), Nlower-alkylaminocarbamyl (N-lower-alkyl hydrazido), Nlower-alkylidenehydrazono, aminomethyl, N lower alkylaminomethyl,N-lower-alkenylaminornethyl, N,N di lower-alkylaminomethyl,N,N-dilower-alkenylaminomethyl, N-lower-alkylamino,N,N-dilower-alkylamino, and N,N-di-lower-alkenylamino; and n representsthe integer 1 or 2.

In the above general Formulas 1a, b, and c, Alk representslower-alkylene containing from two to seven carbon atoms and interposingfrom two to six carbon atoms between the indolyl group and the nitrogenatom of the piperidine ring. The lower-alkylene group can be straight orbranched and thus represents, inter alia, 1,2-ethylene [CH CH1,3-propylene[CH CH CH 1,2- l-methylethylene) [CH (CH CH 1 ,4-butylene[CH CH CH CH 1,3 (l-methylpropylene) [-CH(CH )CH CH 1,2- (lethylethylene) [CH(C H )CH 1,5 pentylene [CH CH CH CH CH 1,4 (3methylbutylene) [-CH CH CH(CH )CH 1,4 (2,4 dimethylbutylene) [-CH(CH )CHCH(CH )CH and the like.

In the above general Formulas la, b, and 0, R represents from one to twomembers of the group consisting of hydrogen, hydroxy, lower-alkoxy,methylenedioxy, lower-alkylmercapto, lower-alkylsulfonyl, or benzyloxy.When R represents two of said groups, the groups may be the same ordifferent and can occupy any of the four available positions on thebenzene ring. When R represents lower-alkoxy, lower-alkylmercapto, orlower-alkylsulfonyl, the lower-alkyl moiety of said groups can containfrom one to about four carbon atoms and can be either straight orbranched. R thus represents, inter alia, methoxy, ethoxy, 2-propoxy,methylmercapto, ethylmercapto, Z-butylmercapto, methylsulfonyl,ethylsulfonyl, 2- butylsulfonyl, and the like.

In the above general Formulas la, b, and 0, when R or R representlower-alkyl, the lower-alkyl group can contain from one to about fourcarbon atoms and can be either straight or branched. R and R each thusrepresent, inter alia, methyl, ethyl, isopropyl, n-butyl, and the like.

When R represents monocarbocyclic aryl or when R representsmonocarbocyclic aryl-lower-alkyl, the monocarbocyclic aryl moietythereof represents phenyl or phenyl substituted by one or moresubstituents such as, for example, halogen (including fluorine,chlorine, bromine, and iodine), lower-alkyl hydroxy, lower-alkoxy,methylenedioxy, lower-alkylmercapto, lower-alkylsulfinyl,lower-alkylsulfonyl, and the like. When the monocarbocyclic aryl moietyis substituted by more than one of the above substituents, thesubstituents can be the same or different and can occupy any of theavailable positions on the phenyl ring. When the substituent is aloweralkyl, lower-alkoxy, lower-alkylmercapto, lower-alkylsulfinyl, orlower-alkyls-ulfonyl group, said substituents can be either straight orbranched and can contain from one to about four carbon atoms. When Rrepresents mono- =carbocyclic aryl-lower-alkyl, the lower-alkyl part ofsaid group contains from one to two carbon atoms. Thus R representsbenzyl or phenethyl and R represents phenyl, or each of such groupssubstituted in the phenyl ring by one or more of such substituents,inter alia, as fluoro, chloro, bromo, iodo, methyl, isobutyl, hydroxy,methoxy, n-butoxy, me-thylenedioxy, methylrnercapto, isopropylmercapto,methylsulfinyl, isopropylsulfinyl, methylsulfonyl, isopropylsulfonyl,and the like.

In the general Formulas la, b, and c, R represents hydrogen or from oneto five lower alkyl radicals. When R represents one or more lower-alkylradicals, each lower-alkyl radical can contain from one to about fourcarbon atoms, can be straight or branched and can occupy any of the fiveavailable positions on the piperidine ring, and when R represents morethan one lower-alkyl radical, said lower-alkyl radicals can be the sameor difierent and can occupy the same or different positions on thepiperidine ring. Thus R represents, inter alia, methyl, ethyl,isopropyl, n-butyl, isobutyl, and the like.

When R represents hydroxy, lowe-r-alkanoyloxy, monocarbocyclic aroyloxy,N-lower-alkylamino, N,N-di-loweralkylamino, N,N-di-lower-alkenylamino,or lower-alkanoylamino, said radicals can occupy either the 3- or 4-.positions of the piperidine ring. When R representshydroxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, monocarbocyclicaroyloxy-lower-alkyl, cycloalkyl-lower-akyl, carbo-loWer-alkoxy,substi-tuted-carbamyl, N-loWer-alkylcarbamyl, N-lower-alkenylcarbamyl,N,N-di-lower-alkylcarbamyl, N,N-di-loweralkenylcarba-myl, aminocarbamyl,N-lower-alkylaminocarbamyl, N-lower-alkylidenehydrazono, aminomethyl,N-lower alkylaminomethyl, N-loweralkenylaminomethyl,N,N-di-lower-alkylaminomethyl, or N,N-di-lower-alkenylaminomethyl, saidradicals can occupy any of the three available positions of thepiperidine ring.

When R represents hydroxy-lower-alkyl, lower-alkanoyloxy-lower-alkyl, ormonocarbocyclic aroyloXy-loweralkyl, the hydroxy-lower-alkyl oroxy-lower-alkyl moiety can be straight or branched and can contain fromone to about six carbon atoms. R thus stands, inter alia, forhydroxymethyl, l-hydroxethyl, 2-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, S-hydroxypentyl, 6-hydroxyhexyl, and the like.

When R represents a loWer-alkanoyloxy ester of a hydroxy orhydroxy-lower-alkyl radical, or when R represents a lower-alkanoylaminoradical, the lower-alkanoyl portion of said radicals can be eitherstraight or branched and can contain from one to about six carbon atoms.R thus also stands, inter alia, for formyloxy, 2-formyloxy ethyl,'acetoxy, Z-acetoxy ethyl, propionoxy, 2-propionoxy ethyl, hexanoyloxy,2-hexanoyloxy ethyl, a-ethylbutyroxy, 2-(a-ethylbutyroxy)ethyl,formylamino, acetylamino, propionylamino, a-ethylbutyrylamino, and thelike.

When R represents cycloakyl-lower-alkyl, the cycloakyl moiety containsfrom five to seven ring carbon atoms, and the lower-alkyl moietycontains from one to two carbon atoms. Thus the cycloalkyl-lower-alkylradical includes such radicals as cyclopentylmethyl, cyclohexylmethyl,2-(cyclohexyl) ethyl, cycloheptylmethyl, and the like.

When R represents a carbo-lower-alkoxy radical, it represents a radicalof the formula COOR' where R is a lower-alkyl group having from one toabout six carbon atoms. Thus the carbo-lower-alkoxy radical includessuch radicals, inter alia, as carbomethoxy, carboethoxy, carbopropoxy,carboisopropoxy, carbobutoxy, carbohexoxy, and the like.

When R represents a monocarbocyclic aroyloxy or a monocarbocyclicaroyloxy-lower-alkyl radical, the monocarbocyclic aroyl moiety can bebenzoyl or benzoyl substituted by one or more substituents selected fromthe group consisting of halogen (including fluorine, chlorine, bromine,and iodine), lower-alkyl, hydroxy, lower-alkoxy, methylenedioxy,lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, amino,and lower-alkanoylamino. When the monocarbocyclic aroyl moiety issubstituted by more than one of the above substituents, the substituentscan be the same or different and can occupy any of the availablepositions on the benzene ring. When the substituent is lower-alkyl,lower-alkoxy, loWer-alkylmercapto, lower-alkylsulfinyl,lower-alkylsulfonyl, or lower-alkanoylamino, said substituents can beeither straight or branched and can contain from one to about fourcarbon atoms. Thus R also stands, inter alia, for benzoyloxy, 2-(4fiuorobenzoyloxy)ethyl, 2-(2 chlorobenzoyloxy)ethyl,3-(4-bromobenzoyloxy)propyl, 6-(4-iodobenzoyloxy)hexyl,3-methylbenzoyloxy, 3-(4-isobutylbenz0 yloxy)propyl,4-hydroxybenzoyloxy, 4 methoxybenzoyloxy, 4-n-butoxybenzoyloxy,3,4-methylenedioxybenzoyloxy, 4-methylmercaptobenzoyloxy,4-isopropylmercaptobenzoyloxy, 4-methylsulfinylbenzoyloxy,4-isopropylsulfinylbenzoyloxy, 4-methylsulfonylbenzoyloxy,4-isopropylsulfonylbenzoyloxy, 2-(4-aminobenzoyloxy)ethyl, 2-(4-acetylaminobenzoyloxy)ethyl, 3-(3,4-dimethoxybenzoyloxy)'propyl,3-(3-chloro-4-methylbenzoyloxy)propyl, and the like.

When R represents N-lower-alkylcarbamyl, N,N,-dilower-alkylcarbamyl,N-lower-alkylaminocarbamyl, N- lower-alkylaminomethyl,N,N-di-lower-alkylaminomethyl, N-lower-alkylamino, orN,N-di-lower-alkylamino, the alkyl moiety in each of said radicals cancontain from one to about four carbon atoms and can be either straightor branced. Thus R also represents, inter alia, N-meth ylcarbamyl,N-ethylcarbamyl, N-butylcarbamyl, N,N-dimethylcarbamyl,N,N-diethylc-arbarnyl, N,N-dibutylcarbamyl, N-ethylaniinocarbamyl,N-ispropylaminocarbamly, N-methylaminomethyl, N-ethylaminomethyl,N-butylaminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl,N-methylamino, N-ethylamino, N,N-dimethylarnino, N,N-diethylamino, orN,N-dibutylamino.

When R represents N-lower-alkenylcarbamyl, N,N-dilower-alkenylcarbamyl,N-lower-alkylidenehydrazono, N- lower-alkenylaminomethyl,N,N-di-lower-alkenylaminomethyl, or N,N-di-lower-alkenylamino, thelower-alkenyl or lower-alkylidcne moiety of said radicals can containfrom three to four carbon atoms and can be straight or branched. Thus Ralso stands, inter alia, for N-2-propenylcarbarnyl,N-Z-methyl-Z-propenylcarbamyl, N,N-di- (2-propenyl) carbamyl, N,N-di-(2-methyl-2-propenyl) carbamyl, 2 propylidenehydrazono, N 2propenylaminomethyyl, N-Z-methyl-Z-propenylaminomethyl, N-N-di-(Z-propenyl)aminomethyl, N,N-di (3-methyl2 propenyl) aminomethyl, orN,N-dipropenylamino.

The compounds of Formula la, b, and c, where R; is hydroxy, hydroxylower-alkyl, cycloalkyl lower-alkyl, aminomethyl,N-lower-alkylaminomethyl, N-lower-alkenylaminomethyl,N,N-di-lower-alkylaminomethyl, N,N,- di-lower-alkenylaminomethyl,N-lower-alkylamino, N,N,- di-lower-alkylamino, orN,N-di-lower-alkenylamino are prepared by reacting with an alkali metalaluminum hydride a respective l-[(3-indolyl)-lower-alkanoyl]piperidine,1-[(3-indolyl)-lower-alkanoyl]-lower-alkylated-piperidine,1-[(2-indolyl)-lower-alkanoyl]piperidine, l-[2 indolyl) lower-alkanoyl]lower-alkylated-piperidine, 1- l-indolyl Jower-alkanoyl] piperidine, or1- 1-indo1yl)- lower-alkanoyl]-lower-alklated-piperidine having theformulas (Ila) N R3 R4 iiud-Oo-N R5 (He) and which are thus representedby the composite formula -11: M t -3. R.

N Alk-CO-N :2

where any one of the three free valences on the indole ring is taken upby the 1-[lower-alkanoyl]piperidine group and the valences at the 1- and2-positions, when not taken up by the 1-[lower-alkanoyl]piperidinegroup, are taken up by the groups R and R respectively, and Where R R RR and n have the meanings given above, All-1 is lower-alkylenecontaining from one to six carbon atoms and interposing from one to fivecarbon atoms between the indolyl group and the carbonyl carbon atom ofthe lower-alkanoyl group, and R is hydroxy, lower-alkanoyloxy,monocarbocyclic aroyloxy, hydroxylower-allay],lower-alkanoyloxy-lower-alkyl, monocarbocyclic aroyloXy-loWer-alkyl,cycloalkyl-lower-alkyl, carbolower-alkoxy, unsubstituted-carbamyl,N-lower-alkylcarbamyl, N-lower-alkenylcarbamyl,N,N-di-lower-alkylcarbamyl, N,N-di-lower-alkenylcarbamyl,N,N-di-loWer-alkylaminomethyl, N,N-di-lower-alkenylaminomethyl,lower-alkanoylamino, N,N-di-lower-alkylamino, orN,N-diloWer-alkenylarnino. The reaction is carried out at a temperaturein the range from about 0 C. to about 65 C. in an organic solvent inertunder the conditions of the reaction. It is preferred to use lithiumaluminum hydride.

The intermediate 3-, 2-, and l-indolyl-lower-alkanoylamides of Form-ulasIla, b, and a above are prepared by reacting a 3-, 2-, orl-indolyl-lower-alkanoic acid With a lower-alkyl haloformate in thepresence of an acid-acceptor, for example triethylamine, at atemperature between about 20 C. and 20 C. to give a mixed anhydride of alower-alkyl carbonic acid and the 3-, 2-, or l-indolyl-lower-alkanoicacid. The latter have the Formulas VIIa, b, and c (VIIa) (at). I O

N Alkoh0-A1k 1 (VIIb) on i l i it Alk- OO-O-A1kyl (VIIC) and are thusrepresented by the composite formula C R2 (R1). L O I,

III -Alk- -o-d-oaum Where any one of the three free valences on theindole ring is taken up by the Alk'-COO-COO-Alkyl group and the valencesat the 1- and 2- positions, when not taken up by the Alk-COOCOO-Alkylgroup, are taken up by the groups R and R respectively, and where R R RR Alk', and n have the meanings given above and Alkyl representslower-alkyl containing from one to about five carbon atoms. The reactionis preferably carried out in an organic solvent inert under theconditions of the reaction such as anhydrous acetone, ether, ethylenedichloride, and the like. Acetone is the preferred solvent. The purposeof the acid-acceptor is to take up the hydrogen halide split out duringthe course of the reaction and is -a basic substance which formswater-soluble byproducts easily separable from the product.

The indolyl-lower-alkane mixed anhydrides of the (1-, 2- and3-indolyl)-lower-all anoic acids of Formulas VIIa, b, and 0 thus formedin situ are reacted with an appropriate piperidine orlower-alkylated-piperidine at a temperature between about -20 C. andabout 20 C. to give the 1-[-(3-indolyl)-lower-alkanoyl]piperidine,1-[(3-indolyl) lower alkanoyl]-lower-alkylated-piperidine, 1-[(2-indolyl -lower-alkanoyl] piperidine, 1- (Z-indolyl -loweralkanoyl] loweralkylated-piperidine, 1-[(1-indolyl)- loWer-alkanoyl]piperidine or1-[(1-indolyl)-lower-alkanoyl]-loWer-alkylated-piperidine of FormulasIla, b, and c.

The compounds of Formula la Where Alk is the 1,2- ethylene group (CH CHR is hydrogen, and R is hydroxy, hydroXy-loWer-alkyl,cycloalkyl-lower-alkyl, aminomethyl, N-lower-alkylaminomethyl, N-loweralkenylaminomethyl, N,N-di-lower-alkylaminomethyl,N,N-dilower-alkenylaminomethyl, N-lower-alkylamino, N,N-diloweralkylamino, or N,N-di-lower-alkenylamino are prepared by reacting withan alkali metal aluminum hydride a respective1-[(3-indo1yl)glyoxalylJpiperidine or 1-[(3-indolyl)glyoxalyl]-lower-alkylated-piperidine having the formula Where RR R and n have the meanings given above and R is hydroxy,lower-alkanoyloxy, monocarbocyclic aroyloxy, hydroxy-lower-alkyl,lower-alkanoyloxy lower-alkyl, monocarbocyclic aroyloxy-lower-alkyl,cycloalkyl-lower-alkyl, carbo-lower-alkoxy, unsubstitutedcarbamyl,N-lower-alkylcarbamyl, N-lower-alkenyl-carbamyl,N,N-di-lower-alkylcarbamyl, N,N-di-lower-alkenylcarbamyl, N,Ndi-loWer-alkylaminomethyl, N,N-dilower alkenylaminomethyl,N,N-di-lower-alkylamino, or N,N-di-loweralkenylamino. The reaction iscarried out at a temperature in the range from about 0 C. to about C. inan organic solvent inert under the conditions of the reaction. Itispreferred to use lithium aluminum hydride.

The intermediate glyoxamides of Formula Illa are prepared by reacting anindole with a glyoxalyl halide at a temperature in the range from about--20 C. to 25 C. in an organic solvent inert under the conditions of thereaction, such as ether, petroleum ether, dioxane, tetrahydrofuran, andthe like thus affording the 3-indolylglyoxalyl halides of Formula IVa.The latter are then reacted With a piperidine orlower-a1kylated-piperidine of Formula V at a temperature in the rangefrom about -5 C. to aobut 65 C. in the presence of an acid-acceptor togive the 1[( 3-indolyl)glyoxalyl] piperidines or 1- [(3indolyl)glyoXlyl] lower alkylated-piperidines of Formula IlIa. Thereaction is represented by the equation:

0 O Clo-H31 N Ra H (Iva) (V) where R R R R and n have the meanings givenabove, and Hal represents halogen. The reaction is preferably carriedout in an organic solvent inert under the conditions of the reaction,for organic tetrahydrofuran, ether ethylene dichloride, and the like.The purpose of the acidacceptor is to take up the hydrogen halide whichis split out during the course of the reaction. The acid-acceptor is abasic substance which forms water-soluble byproducts easily separablefrom the main product of the reaction and includes such substances asalkali metal salts of weak acids, e.g. sodium carbonate, sodiumbicarbonate, potassium carbonate, sodium acetate, and the like. Theacid-acceptor can also be in the form of an excess quantity of thepiperidine or lower-alkylated-piperidine. A preferred solvent istetrahydrofuran, and it is preferred to use an excess quantity of thepiperidine or lower-alkylated-piperidine as the acid-acceptor.

When R in the compounds of Formulas IIa, b, and c and IIIa is anon-reducible group, for example hydroxy, hydroxy lower-alkyl,cycloalkyl lower-alkyl, N,N-dilower alkylamino orN,N-dilower-alkenylamino, the respective compounds of Formulas In, 17,or c are produced in which the group R remains unchanged in thereaction. But when R in the compounds of Formulas IIa, b, and c, orFormula IIIa is a reducible group, the group R is reduced simultaneouslywith the alkanoyl carbonyl group or the glyox-alyl group thus producingproducts of Formulas Ia, b, and c in which the piperidyl group issubstituted by the group R in a reduced state. In such cases anadditional amount of the alkali metal aluminum hydride must be used inthe reaction mixture to insure the complete reduction of both the Rsubstituent and the carbonyl groups of the lower-alkanoyl or glyoxalylradicals. Thus a one molar equivalent of an alkali metal aluminumhydride, in addition to the one molar equivalent required to reduce thelower-alkanoyl carbonyl group or the two molar equivalents required toreduce the glyoxalyl group, would reduce a lower-alkanoyloxy group or amonocarbocyclic aroyloxy group to the hydroxy group, alower-alkanoyloxy-lower-alkyl or a monocarbocyclic aroyloxy-lower-alkylgroup to a hydroxy-lower-alkyl group, a carbo-lower-alkoxy group to thehydroxymethyl, i.e., a hydroxy-lower-alkyl group, theunsubstituted-carbamyl group to the aminomethyl group, anN-lower-alkylcarbamyl group to an N-lower-alkylaminomethyl group, anN-lower-alkenylcarbamyl group to an N-lower-alkenylaminomethyl group, anN,N-di-lower-alkyl-carbamyl group to an N,N-d-i-lower-alkylaminomethylgroup, an N, N-di-lower-alkenylcarbamyl group to anN,N-di-loweralkenylaminomethyl group, or a lower-alkanoylamino group toan N-lowenalkylamino group.

The compounds of Formulas Ia, b, and c where R is hydroxy,lower-alkanoyloxy, monocarbocyclic aroyloxy, hydroxy lower alkyl,lower-alkanoyloxy-lower-alkyl, monocarbocyclic aroyloxy lower-alkyl,cycloalkyl-loweralkyl, carbo lower-alkoxy, unsubstituted-carbamyl, N-lower alkylcarbamyl, N lower-alkenyl-carbamyl, N,N- di loweralkylcarbamyl, N,N-di-loweralkenylcarbamyl, N lower alkylidenehydrazono,or lower-alkanoylamino are prepared by reacting a (1-, 2- or 3-indolyl)-lower-alkyl halide (Formulas VIa, b, 0 below) with the appropriatelysubstituted piperidine or lower-alkylated piperidine (Formula V) at atemperature between about 50 and 150 C. in the presence of anacid-acceptor. The reaction is represented by the following equation:

8 where R R R R R 11, and Alk have the meaning given above and Hal ishalogen.

The reaction is preferably carried out in an organic solvent, inertunder the conditions of the reaction, for example, anhydrous ethanol,benzene, xylene, and the like. The purpose of the acid-acceptor is totake up the hydrogen halide which is split out during the course of thereaction. The acid-acceptor is a basic substance which formswater-soluble by-products easily separable from the main product of thereaction and includes such substances as alkali metal salts of weakacids, e.g., sodium carbonate, sodium bicarbonate, potassium carbonate,sodium acetate, sodium alkoxides, and the like. The acidacceptor canalso be in the form of an excess quantity of the piperidine orlower-alkylated-piperidine.

The compounds of Formula Ia where R is a hydrogen atom and R is hydroxy,hydroxy-lower-alkyl, lower-alkanoyloxy, monocarbocyclic aroyloxy,lower-alkanoyloxylower-alkyl, monocarbocyclic aroyloxy-lower-alkyl,cycloalkyl-lower-alkyl, unsubstituted-carbamyl, N-lower-alkylcarbamyl, Nlower-alkenylcarbamyl, N,N-di-loweralkylcarbamyl, N,N dilower-alkenylcarbamyl, N,N- di lower-alkylaminomethyl,N,N-di-lower-alkenylaminomethyl, N,N-di-lower-alkylamino, orN,N-di-lower-alkenylamino are also prepared by reacting phenylhydrazineor an appropriately substituted-phenylhydrazine with a 1- (a-formyllower alkyl)-substituted-piperidine, al-(wlower-alkanoyl-lower-alkyl)substituted-piperidine, or a 1-(w-monocarbocyclic aroyl-lower-alkyl -substituted-piperiink-N (R1) I \N/Ra The reaction, known as the Fischer indole reaction, takes place intwo steps with the formation of the hydrazone of Formula VIII occurringin the first step. The hydrazone then rearranges, under the conditionsof the reaction, with loss of a molecule of ammonia to form thecompounds of Formula la.

The reaction is carried out at a temperature in the range from about 20C. to about 150 C. in an organic solvent inert under the conditions ofthe reaction, for example, ethanol, methanol, isopropanol, glacialacetic acid, and the like and in the presence of an acid catalyst, forexample, sulfuric acid, hydrochloric acid, glacial acetic acid, zincchloride, cuprous chloride, or boron trifluoride.

The compounds of Formulas Ia, b, and c; Ila, b, and c; and IIIa where Ris aminocarbamyl (hydrazido) are prepared by reacting the respectivecompounds of Formulas Ia, b, and c; Ila, b, and c; and Illa where R iscarbo-lower-alkoxy with a molar excess of hydrazine hydrate at atemperature in the range from about C. to about 120 C. Although it ispreferred to use hydrazine hydrate, aqueous solutions of hydrazinehydrate can also be used successfully, for example, commerciallyavailable 80% solutions.

The compounds of Formulas la, b, and c; Ila, b, and c; and Illa where Ris N-lower-alkylidene hydrazono are prepared by reacting the respectivecompounds of Formulas la, b and c; Ila, b, and c; and HM where R isaminocarbamyl (hydrazido) with a lower-aliphatic aldehyde ordi-lower-alkyl ketone at a temperature in the range from about 50 C. toabout l5{} C.

The compounds of Formulas la, b, and c; Ila, b, and c; and Illa where Ris N-lower-alkylaminocarbamyl are prepared by reducing with hydrogenover a catalyst the respective compounds of Formulas la, b, and c; Ila,b, and c; and Illa where R is N-lower-alkylidene hydrazono. The reactionis carried out in an organic solvent inert under the conditions of thereaction, for example methanol, ethanol, isopropanol, and the like, at atemperature in the range from about C. to about 75 C. and at hydrogenpressures in the range from about 5070 pounds p.s.i. A preferredcatalyst is platinum oxide.

The intermediate indolyl-lower-alkyl halides of Formulas VIa, b, and cused as intermediates in the method described above are prepared byreduction of a l-, 2-, or 3-indolyl-lower-alkanoic acid with lithiumaluminum hydride and conversion of the resulting alcohol to thecorresponding halide by reacting the former with, for example, aphosphorous trihalide of a thionyl halide.

The compounds of Formulas la, b, and c where R is the 4-hydroxy groupcan also be prepared by any of the above general procedures by reacting4-piper-idone or a lower-alkylated-4-piperidone with a lower-alkanemixed anhydride of a 3-, 2-, or l-indolyl-lower-alkanoic acid to give a1-[(3-, 2-, or l-indolyl)-lower-alkanoyl]-4-piperidone orlower-alkylated-4-piperidone; by reacting 4- piperidone or alower-alkylated-4-piperidone in the presence of an acid-acceptor with a(3-, '2-, or 1-indolyl)- loWer-alkyl halide to give a 1-[ (3-, 2-, orl-indolyl)-loweralkyl]-4-piperidone tor loWer-alkylated-4-piperidone; byreacting a 4-piperidone or lower-alkylated-4-piperidone in the presenceof an acid-acceptor with a 3-indolylg-lyoxalyl halide to give al-[(3-indolyl)-glyoxalyl]-4-piperidone or lower-alkylated-4-piperidone;or by reacting phenylhydrazine or a substituted-phenylhydrazine with a1-(wformyl-lower-alkyl)-4-piperidone, al-(w-lower-alkanoyllower-alkyl)-4-piperidone, or a l-(w-monocarbocyclicaroyl-loWer-alkyl)-4-piperidone and reacting the product in each casewith an alkali metal aluminum hydride to reduce the 4-carbonyl group ofthe 4-piperidone or loweralkylated-4-piperidone ring to the 4-hydroxygroup.

The novel compounds of the instant invention are the compounds ofFormulas la, b, and 0; Ha, b, and c; and Illa and the acid-addition andquaternary ammonium salts of the former. The compounds of Formulas la,b, and c in free base form are converted to the acid-addition salt formby interaction of the base with an acid. In like manner, the free basescan be regenerated from the acid-addition salt form in the conventionalmanner, that is, by treating the salts with strong aqueous bases, forexample alkali metal hydroxides, alkali metal carbonates, and alkalimetal bicarbonates. The bases thus regenerated can then be interactedwith the same or a different acid to give back the same or a differentacid-addition salt. Thus the novel bases and all of their acid-additionsalts are readily inter-convertible.

It will thus be appreciated that each of Formulas la, b, and c not onlyrepresents the structural configuration of the bases of Formulas la, band 0 but each is also representative of the respective structuralentity which is common to all of my respective compounds of Formulas la,b, and c, whether in the form of the free bases or in the form of theacid-addition salts of the bases. I have found that by virtue of thiscommon structural entity, the bases and their acid-addition salts haveinherent pharmacodynamic activity of a type to be more fully describedhereinbelow. This inherent pharmacodynamic activity can be enjoyed inuseful form for pharmaceutical purposes by employing the free basesthemselves or the acid-addition salts formed from pharmaceuticallyacceptable acids, that is, acids Whose anions are innocuous to theanimal organism in effective doses of the salts so that beneficialproperties inherent in the common structural entity represented by thefree bases are not vitiated by side-effects ascribable to the anions.

In utilizing this pharmaoodynamic activity of the salts of theinvention, I prefer of course to use pharmaceutically-acceptable salts.Although Water-insolubility, high toxicity, or lack of crystallinecharacter may make some particular salt species unsuitable or lessdesirable for use as such in a given pharmaceutical application, theWaterinsoluble or toxic salts can be converted to the correspondingpharmaceutically-acceptable bases by decomposition of the salt withaqueous base as explained above, or alternatively, they can be convertedto any desired pharmaceutically acceptable acid-addition salt by doubledecomposition reactions involving the anion, for example, byion-exchange procedures.

Moreover, apart from their usefulness in pharmaceutical applications, mysalts are useful as characterizing or identifying derivatives of thefree bases or in isolation or purification procedures. Like all of theacidaddition salts, such characterizing or purification salt derivativescan, if desired, be used to regenerate the pharmaceutically acceptablefree bases by reaction of the salts with aqueous base, or alternativelycan be converted to a pharmaceutically acceptable acid-additi-on saltby, for example, ion-exchange procedures.

It will be appreciated from the foregoing that all of the acid-additionsalts of my new bases are useful and valuable compounds, regardless ofconsiderations of solubility, toxicity, physical form, and the like, andare accordingly within the purview of the instant invention.

The novel feature of the compounds of the invention, then, resides inthe concept of the bases and cationic forms of the new 1-[(3-, 2-, and1-indolyl)-lower-alkyl] piperidines and not in any particular acidmoiety or acid anion associated with the salt forms of my compounds;rather, the acid moieties or anions which can be associated in the saltforms are in themselves neither novel nor critical and therefore can beany acid anion or acid-like substance capable of salt formation withbases. In fact, in aqueous solutions, the base form or water-solubleacidaddition salt form of the compounds of the invention both possess acommon protonated cation or ammonium ion.

Thus the acid-addition salts discussed above and claimed herein areprepared from any organic acid, inorganic acid (including organic acidshaving an inorganic group therein), or organo-metallic acid asexemplified by organic monoand polycarboxylic acids; such as found, forexample, in Beilsteins Organische Chemie, 4th ed., volumes III, IV, IX,X, XIV, XVII, XIX, XXI, XXII, and XXV; organic monoand polysulfonic andsulfinic acids; such as found, for example, in Beilstein, volumes VI,XI, XVI, and XXII; organic phosphonic and phosphinic acids; such asfound, for example, in Beilstein, volumes XI and XVI; organic acids ofarsenic and antimony; such as found, for example, in Beilstein, volumeXVI; organic heterocyclic carboxylic, sulfonic, and sulfinic acids suchas found, for example, in Beilstein volumes XVIII, XXII, and XXV; acidicion-exchange resins, for example Amberlite XE-66 resin; and inorganicacids of any acid forming element or combination of elements, such asfound in Mellor, Comprehensive Treatise on Inorganic and TheoreticalChemistry, Longmans, Green and Co., New York, N.Y., volumes I-XVI. Inaddition, other salt-forming compounds which are acidic in theirchemical properties but which are not generarly considered as acids inthe same sense as carboxylic or sulfonic acids are also considered to beamong the numerous acids which can be used to prepare acid-additionsalts of the compounds of the invention. Thus there is also comprehendedacidic phenolic. compounds, such as found, for example, in Volume VI ofBeilstein, acidic compounds having activated or acidic hydrogen atoms,as for example, picro- Ionic acid, or barbituric acid derivatives havingan acidic proton, such as found, for example, in Cox et al., MedicinalChemistry, vol. IV, John Wiley and Sons, Inc., New York, NY. (1959).Also comprehended as salt forming agents are so-called Lewis acids whichlack a pair of electrons in the outer electron shell and react withbasic compounds having an unshared pair of electrons to form salts, forexample boron trifluoride.

Thus appropriate acid-addition salts are those derived from such diverseacids as formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid,succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid,4-methoxybenzoic acid, phthalic acid, anthranilic acid,l-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid,mandelic acid, tropic acid, crotonic acid, acetylene dicarhoxylic acid,sorbic acid, Z-furancarboxylic acid, cholic acid, pyrenecarboxylic acid,2-pyridinecarboxylic acid, 3-

-indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid,isethionic acid, benzenesulfonic acid, p-

toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid,diethylphosphinic acid, p-aminophenylarsinic acid, phenylstibnic acid,phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid,Amberlite XE-66 resin, hydrofluoric acid, hydrochloric acid, hydrobromicacid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid,phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid,phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid,picrolonic acid, barbituric acid, boron trifiuoride, and the like.

The acid-addition salts are prepared either by dissolving the free basein an aqueous solution containing the appropriate acid and isolating thesalt by evaporating the solution, or by reacting the free base and acidin an organic solvent, in which case the salt separates directly or canbe obtained by concentration of the solution.

The quaternary ammonium salts of the compounds of Formulas Ia, b, and care obtained by the addition of esters of strong acids to the free baseform of the com pounds, said esters having a molecular weight less thanabout 300. A preferred class of esters comprises alkyl, alkenyl, andmonocarbocyclic aryl-lower-alkyl esters of strong inorganic acids ororganic sulfonic acids, including such compounds as methyl chloride,methyl bromide, methyl iodide, ethyl bromide, propyl chloride, allylchloride, allyl bromide, methyl sulfate, methyl benzenesulfonate, methylp-toluenesulfonate, benzyl chloride,.benzyl bromide, and substitutedbenzyl halides, for example p-chlorobenzyl chloride, 3,4-dichlorobenzylchloride, pentachlorobenzyl chloride, p-nitrobenzyl. chloride,methoxybenzyl chloride, and the like.

The quaternary ammonium salts are prepared by mixing the free base andester of a strong acid in an inert solvent. Heating may be used tofacilitate the. reaction, although salt formation usually takes placereadily at room temperature. The quaternary ammonium salt separatesdirectly or can be obtained by concentration of the ,salts by doubledecomposition reactions involving the anion, for example, byion-exchange procedures. Alternatively, if the anion of the originalquaternary salt forms a water-insoluble silver salt, the quaternary saltwill react with silver oxide in aqueous medium to form the correspondingquaternary ammonium hydroxide, the

original anion being removed as a precipitate. The quaternary ammoniumhydroxide solution can then be neutralized with any desired acid, weakor strong, to produce a new quaternary ammonium salt in which the anionis diiferent from that of the original salt. In this way quaternaryammonium salts in which the anion is derived from a weak acid areformed.

Pharmacological evaluation of the compounds of Formulas Ia, b, and 0have shown that they possess pharmacodynamic and chemotherapeuticproperties, in particular, hypotensive, sedative, anti-inflammatory,monoamine oxidase inhibitory, coronary dilator, adrenolytic,tranquilizing, and antibacterial activities thus indicating theirusefulness as blood pressure lowering agents, sedatives,anti-inflammatory agents, psychic energizers, coronary dilators,tranquilizers, and anti-bacterial agents. The compounds of Formulas Ila,b, and c have also been shown to possess hypotensive and coronarydilator activities and are thus useful not only as intermediates in thepreparation of the compounds of Formulas la, b, and 0 but also haveutility as blood pressure lowering agents and coronary dilators.

The compounds can be prepared for use by dissolving under sterileconditions a salt form of the compounds in water (or an equivalentamount of a non-toxic acid if the free base is used), or in aphysiologically compatible aqueous medium such as saline, and stored inampoules for intramuscular injection. Alternatively, they can beincorporated in unit dosage form as tablets or capsules for oraladministration either alone or in combination with suitable adjuvantssuch as calcium carbonate, starch, lactose, talc, magnesium stearate,gum acacia, and the like. Still further the compounds can be formulatedfor oral administration in aqueous alcohol, glycol or oil solutions oroil-water emulsions in the same manner as conventional medicinalsubstances are prepared. When used as hypotensive agents, they areformulated and used in the same manner as conventional hypotensiveagents, such as reserpine preparations, and indeed can be usedadvanatgeously in combination with such hypotensive agents. Thestructures of the compounds of the invention are established by theirmode of synthesis and corroborated 'by the correspondence betweencalculated values for the elements and values found by chemicalanalysis.

The following examples will further illustrate the invention without thelatter being limited thereto.

Example 1 3-[2-(4-hydroxy-1-piperidyl)ethyl]indole [Ia; R R R and R areH, R is 4-OH, Alk is CH- CH A solution of 4.48 g. (0.02 mole) of2-(3-indolyl)ethyl bromide and 4.5 g. (0.04 mole) of 4-hydroxypiperidinein 200 ml. of acetonitrile was heated under reflux for about twentyhours. The cooled solution was decanted from a viscous yellow oil whichhad separated, and the oil washed with two 50 ml. portions ofacetonitrile. The combined acetonitrile solutions were concentrated invacuo giving a viscous yellow oil which was dissolved in ml. of 10%aqueous acetic acid. The acid solution was filtered, basified withconcentrated ammonium hydroxide, and the solid which separated collectedand dried giving 4.55 g. of crude product. The latter, onrecrystallization from ethyl acetate, afforded 2.37 g. of3-[2-(4-hydroxy-1- piperidyl)ethyl]indole, m.p. l44.6-l46.8 C. (corr.).

3-[2-(4-hydroxy-1-piperidyl)ethyl]indole reacts with formic acid, aceticacid, isobutyric acid, alpha-mercaptopropionic acid, malic acid,furnaric acid, succinic acid, succinamic acid, tartaric acid, citricacid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid,anthranilic acid, l-naphthalenecarboxylic acid, cinnamic acid,cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic acid,acetylene dicarboxylic acid, sorbic acid, Z-furancarboxylic acid, cholicacid, pyrenecarbox- .ylic acid, Z-pyridinecarboxylic acid,3-indoleacetic acid,

quinic acid, sulfamic acid, methanesulfonic acid, isethionic acid,benzenesulfonic acid, p-toluenesulfonic acid, benzenesulfinic acid,butylarsonic acid, diethylphosphinic acid, p-aminophenylarsinic acid,phenylstibnic acid, phenylphosphinous acid, methylphosphonic acid,phenylphosphinic acid, Amberlite XE-66, hydrofluoric acid, hydrochloricacid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid,sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid,molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid,picric acid, picrolonic acid, barbituric acid, boron trifluoride, andthe like, to give respectively, the formate, acetate, isobutyrate,alpha-mercaptopropionate, malate (or acid malate), fumarate (or acidfumarate), succinate (or acid succinate), succinamate, tartrate (orbitartrate), citrate (or acid citrate), lactate, benzoate,4-methoxybenzoate, phthalate (or acid phthalate), anthranilate,l-naphthalenecarboxylate, cinnamate, cyclohexanecarboxylate, mandelate,tropate, crotonate, acetylene dicarboxylate, sorbate (or acid sorbate),Z-furancarbox- 20 phosphate (or acid phosphate), hydrocyanide,phosphotungstate, molybdate, phosphomolybdate, pyrophos phate, arsenate,picrate, picrolonate, barbiturate and boron trifluoricle salts.

3-[2-(4-hydroxy-l-piperidyl)ethyl]indole can be reacted with hydriodicacid to form 3-[2-(4-hydroxy-lpiperidyl)ethyl]indo1e hydriodide, usefulas a characterizing intermediate.

3-[2-(4-l1ydroxy-l-piperidyl)ethylJindole, in the form of itshydriodidesalt, can be converted to the hydrochloride salt by passing anaqueous solution of the former over an ion-exchange resin saturated withchloride ions, for example Rohm & Haas Amberlite IRA-400 resin.

3-[2-(4-hydroxy-l-piperidyl)ethyl]indole can be reacted with methyliodide, methyl bromide, ethyl bromide, allyl bromide, benzyl chloride,2-chlorobenzyl chloride, 2,3,4,5,6-pentachlorobenzyl chloride, or methylp-toluenesulfonate to give the methiodide, methobromide, ethobromide,allobromide, benzochloride, Z-chlorobenzochloride,2,3,4,5,6-pentachlorobenzochloride, or metho-p-toluenesulfonate salts,respectively.

The compounds of Formulas Ia and la listed in Table 1 below wereprepared according to the procedure described above in Example 1 from anappropriate (3- or 1-indolyl)-loWer-alky1 halide and an appropriatesubstituted-piperidine. All melting points are corrected unless notedotherwise. The compounds of Formula 10 are indicated by an asterisk TABLE 1 Example R5/Alk Base or M.P./cryst. fromsalt 230.O 235.4 C.isopropanol.

{160.6-1632" C. ethyl acetate. {101.4l02.2 C. ethyl acetate/hexane.nan-118.8 o. ethyl acetate. {176.8184.3 C. methanol. 109.4-1142" C.ethyl acetate. {140.6-143A" C. acetonitrile. 143.0-1442 C. acetonitrile.l12.41l5.8 C. ethyl acetate. {129.2-130A" C. ethyl acetate/hexane.

{139.844'18 o. ethyl acetate/hexane. 180.4-1818" C. isopropanol.110.4l11.8 O. acetone/ hexane. IBIS-110.4 0. ben- Zena/hexane.{125.2126.8 O. acetone} hexane.

{130.6132.4 C. methanol. 116.21l8.0 C. ethanol] ether. {182.6-184.0 C.ethyl acetate. 166.8-1692 C. ethyl l iis 0 h 1 166. 1 .6 et y acetat e.4-CON(C2HO 139.2140.4 C. ethyl CH2 1 acetate.

l39.8l40.6 C. ethyl (011m acetate/hexane. 4CONHCzH5 do {147.0-1482 C.ethyl (CH2); acetate/hexane. z-(ggglHz do {126.8t127.8 C. ethyl 2 a" aceate 4-CONHCH3 do {1042-106 0 C ((LHilw.v isopropanol. 4-CONHC2H5-1062-1068 C. on; hexane. 2-CONHC2H5 do {71.2-73.0 0. (CHz)s ethylacetate/hexane. 4-CHQC5H1] do {143.0l43.8 C. CHZOHZ hexane.

*Compound of Formula Iv.

5 Example 30 3-[2 (4 aminocarbamyl 1 piperidyl)ethyl]indole [111; R1,R2, R3 and R4 are H, R5 is iS A solution of 3.0 g. (0.01 mole) of 3-[2in Example 18 was dissolved in 250 ml. of dry tetrahydrofuran in athree-necked round bottom flask equipped with a dropping funnel, refluxcondenser and mechanical stirrer. To the solution was added withstirring and cool- CHZCHQ]: (4-carbomethoxy-l-piperidyl)ethylJindole, in16 ml. of 5 1 2} qg i g g (1111016) g hydrazine hydrate was heated underreflux for six hours. z g y y i .5 Ta The reaction mixture was thenevaporated to dryness in 23 e a gg 3' 1. vacuo, and the gummy whitecrystalline residue was exg gs; g 2:: 25 x23 2:3 r E2 trated with five50 ml. portions of boiling chloroform. I d d b d The chloroform extractswere filtered, concentrated to 10 l aummum. y n e was ecomppse y ropwlseadditlon of a solution of 6 ml. of water 111 ml. of tetraabout 100 ml.and diluted with 400 ml. of hexane. The h drof ran Th tut W s filteredth filt k solid which separated was collected, washed with cold y h h ei a ca e hexane and recrystallized repeatedly from a chloroforms Wit mPOI Ions o e y m unin hexane mixture giving 3.88 g. of3-[2-(4-aminocarbamyl- F epombmizld Hates were avaporateq m vacuo glvn1- i eridyl)ethvl]indole, M.P. 164.6-166.0 0. (corn). mg a 9 T latterwas taken ether i p p treated with a solution of anhydrous hydrogenchloride Example 31 in ether. The precipitated gummy solid was separatedfrom the supernatant liquid by decantation andrecrystallsopropyhdenehydrazono-ljplpendyllethyll lized from anisopropanol-ether mixture giving 7.67 g. of lndole 1, 2, 3 and 4 are s15 1-[3-(3-hydroxymethyl-1-piperidyl)propyl]indole hydro- 4CONHN:C(CH3)2 chloride, M.P. 127.5133.3 C. (corr.). Alk is crr crr Asolution of 4.0 g. 0.014 mole) of Example 35 y 'p p y y l in 603-[2-(4-ethylamino 1-piperidyl)ethyl]indole dihydroof acetone was heatedunder reflux for seven hours. The 25 chloride [Ia; R R R and R are H, Ris 4-NHC H solid that separated from the cooled reaction mixture was lki CHZCHE]; 3 2 (4 1 i -1- i id 1) h l collected and recrystallized fromethyl acetate giving indole 7 3 g 003 mol) prepared above i Example 20,g of -t p py y 'p p l in 300 ml. of anhydrous tetrahydrofuran, wasreduced ethylllndole, 30 with 3.89 g. (0.10 mole) of lithium aluminumhydride in Emmple 32 150 ml. of dry tetrahydrofuran according to themanipulative procedure described above in Example 34. The 3-[2-(4-isopropylaminocarbamyl 1 piperidyl)ethyl] product was isolated as thefree base and converted to indole [Ia; R R R and R are H, R is thedihydrochloride salt. The latter was recrystallized from anethanol-ether mixture giving 2.3 g. of 3-[2-(4- 3)2 0 ethylamino 1piperidyl)ethyl]indole dihydrochloride. Alk is CH CH About 0.02 mole of3-[2-(4-isopropyl- 259-6462 (dewidenehydrazono-l-piperidyl)ethyl]indole, dissolved in 200 Exam le 36 ml.of methanol, was reduced over 0.2 g. of platinum p oxide under ahydrogen pressure of about 55 pounds psi. 0 [4 (N ethy1amin0methy1) 1pipel-idynethyl} Reduction was complete in about four hours. Thecatindole dihydrochloride R1 R2 R3 and R1 are H R alyst was removed byfiltration. The filtrate was taken is 4 CHZNHC2H5 Alk is was prepared 2to dryness and the resulting solid recrystallized from a 550 (Q02 mole)of 3 {2 [4 (N ethy1carbamy1) 1 chloroform-hexane mixture g ving 2.05 g.of 3-[2-(4-1sopiperidynethynindolea prepared abovg in Example 21 bypropylammofarbamyl 1 plpendynethynmdole, reduction of the latter in 280ml. of dry tetrahydrofuran 1514-1533 (con-L with 1.40 g. (0.04 mole) oflithium aluminum hydride Example 33 in 200 ml. of anhydroustetrahydrofuran according to the manipulative procedure descnbed abovein Example 34. 3-[2-(2 aminocarbamyl 1 piperidyl)ethyl]indole Theproduct was isolated in the form of the free base and [Ia; R R R and Rare H, R is 2-CONHNH Alk converted to the dihydrochloride salt. Thelatter was is CH CH was prepared from 2.63 g. (0.009 mole) ofrecrystallized from a methanol-ether mixture giving 3.183-[2-(Z-carbethoxy-l-piperidyl)ethyl]indole and 6 ml. of g. of3-{2-[4-(N-ethylaminomethyl) 1 -piperidyl]ethyl} 100% hydrazine hydratein 50 ml. of isopropyl alcohol indole dihydrochloride, does not melt upto 290 C. according to the manipulative procedure described above inExample 30. The product was recrystallized from a Examp 37-40chloroform-hexane mixture giving 1.0 g. of3-[2-(2-arninocarbamyl-1-piperidyl)ethyl]indole, M.P. 138.4-139.8 C. Byiollowmg the mampPlaPve Procedure descnbed (com) above 1n Example 1,substitutingfor the 2-(3-indolyl) Example 34 ethyl bromide and the4-hydroxyp1peridine used therein, molar equivalent amounts of anappropriate 6-(3-iudolyl) 1-[3-(3 hydroxymethyl 1piperidyl)propyl]indole hexyl bromide and an appropriate loWer-alkylatedpiperhydrochloride [10; R R and R are H, R is 3-CH OH, idine, there canbe obtained the compounds of Formula Alk is (CH About 15 g. (0.05 mole)of 1-[3-(3- Ia listed below in Table 2 where R and R in each casecarbomethoxy-1-piperidyl)propyl]indole prepared above are hydrogen andAlk in each case is (CH TABLE 2 (FORMULA Ia) Example R1 R4 R, n

37 fi-HO- 2,4,6-tri-CH 4-110 1 38 5,6-OCHzO--- 2,2,4,6,6-penta-GH;4-110. 1 39 (SCHaS 5-C1H5 2-OHzCHnOH 1 40 6-CHaSO2 2,2-dl-CH -6-(OHmCHCH4-110 1 17 Examples 41-57 By following the manipulative proceduredescribed above in Example 1, substituting for the 4-hydroxypiperidineused therein a molar equivalent amount of an appropriately substitutedpiperidine, there can be obtained the compounds of Formula Ia listedbelow in Table 3, where R R R and R in each case is hydrogen and Alk ineach case is (CH TABLE 3 (FORMULA Ia) Example: R

41 3-CH CH OCCH 42 4-N(I1-C4H9)2- 43 2-CONHCH CH=CH 44 4-N(CH2CH:CH2)2-45 4-C H COO. 46 2-(2-ClC H COOCH CH 47 4-(3-CH C H COO). 48 4-(4-HOC HCO0). 49 4-(4-CH OC H CO0).

50 4-(3,4-( ;CHaO( JeHsC O O).

51 3-(4-CH SC H COO). 52 3-(4-CH SOC H COO). 53 3-(4-CH SO C H COO). 544-(4-CH CONHC H COOCH CH 55 4-[3,4-(CH O) C H COOCH CH CH 564-(3-Cl-4-CH C H COOCH CH CH 57 4C H CH Example 583-{2-[2-(N-allylaminomethyl) 1 piperidyl]ethyl}indole R1, R2, R3 and R4are H, is (CH2)2, R5 is 4 2 CH NHCH CH=CH By reacting the3-{2-[2-(N-allylcarbamyl)-1-piperidyl]-ethyl}indole prepared above inExample 43 with lithium aluminum hydride in an organic solvent inertunder the conditions of the reaction, for example diethyl ether ortetrahydrofuran, there can be obtained 3-{2-[2-(N-allylaminomethyl)-1piperidyl1ethyl} indole.

Example 59 Example 60-76 By following the manipulative proceduredescribed above in Example 1, substituting for the 2-(3-indolyl) ethylbromide used therein, a molar equivalent amount of an appropriate2-(3-indolyl)ethyl halide substituted in the 1- and/ or 2-positions,there can be obtained the compounds of Formula Ia listed below in Table4 where R and R in each case is hydrogen, R in each case is 4-HO, andAlk in each case is CH CH TABLE 4 (FORMULA Ia) Example R2 R3 CaHiCHz aMCu a Hz H.

65 3,4-(OCH2OCuH3CHz) gHa.

HI CtlHB- 4-O1-3-CHaCeHa. 4-HOCsH4. 1 3O)2 al 73 Fl 3,4(OCH2OCH!)- 74 H4-CH3SC6H4. 75 H 4-CH3SOCuH4. 76 l-T 4-CH SOgCaH4.

Example 77 S-chloro-2-[2-(4-hydroxy-1-piperidyl)ethyl]indole [Ib; R isS-Cl, R and R are H, Alk is CH CH and R5 is 4-HO]: By reducing5-chloro-2-indole acetic acid with lithium aluminum hydride in anorganic solvent inert under the conditions of the reaction, for examplediethyl ether or tetrahydrofuran, there can be obtained 5-chloro-2-(2-indolyl)ethanol. By reacting the latter with a phosphoroustrihalide or a thionyl halide, there can be obtained a5-chloro-2-(2-indolyl)ethyl halide. By reacting the latter with twomolar equivalents of 4-hydroxypiperidine following the manipulativeprocedure described above in Example 1, there can be obtained5-chloro-2- [2- (4-hydroxyl-pip eridyl) ethyl] indole.

Example 78 5-methoxy-2-{6-[4-(2 hydroxyethyl) 1 piperidyl] hexyl}indole[111; R is 5-CH O, R and R are H, Alk is (CH and R is 4-CH CH OH]: Byreacting S-methoxy-2-(2-indolyl)ethyl bromide with diethylmalonate inthe presence of sodium ethoxide and saponifying and decarboxylating theproduct thus formed in an alkaline medium, there can be obtained'y-(5-methoxy-2-indolyl) butyric acid. By reducing the latter withlithium aluminum hydride in an organic solvent inert under theconditions of the reaction, for example diethyl ether ortetrahydrofuran, there can be obtained 4-(5-methoxy-2- indolyl)butylalcohol. By reacting the latter with a phosphorous trihalide or athionyl halide, there can be obtained a 4-(5-methoxy-2-indolyl)butylhalide. By reacting the latter with diethylmalonate in the presence ofsodium ethoxide and saponifying and decarboxylating the product thusformed in an alkaline medium, there can be obtainede-(5-methoxy-2-indolyl)hexanoic acid which on reduction with lithiumaluminum hydride gives 6-(5- methoxy-2-indolyl)hexyl alcohol. Byreacting the latter with a phosphorous trihalide or a thionyl halide,there can be obtained a 6-(5-methoxy-2-indolyl)hexyl halide. By reactingthe latter with 4-(Z-hydroxyethylpiperidine), there can be obtained5-methoxy-2-{6-[4-(2-hydroxyethyl 1 -piperidyl] hexyl}indole.

Examples 79-82 By following the manipulative procedure described abovein Example 1, substituting for the 2-(3-indolyl) ethyl bromide and the4-hydroxypiperidine used therein, molar equivalent amounts of anappropriate 6-(2-indolyl) hexyl bromide and an appropriatelower-alkylated piperidine, there can be obtained the compounds offormula Ib listed below in Table 5 where R in each case is hydrogen andAlk in each case is (CH TABLE 5 (FORMULA Ib) Example R1 R4 R5 11.

i9; e110- 2,4,6-tri-CHi Q: 4-110 1 so 545001120--. 2,2,4,6,6-penta-CH4-HO 1 81 6-CH3S 2 5 2-CHnCH2OH 1 s2 s-cmsozmn 2,2-di-CH3-6(CH3)gCI-IOHz- 4-HO 1 Examples 83-98 By following the manipulativeprocedure described above in Example 77, substituting for the4-hydroxypiperidine used therein a molar equivalent amount of anappropriately substituted piperidine, there can be obtained thecompounds of Formula Ib listed below in Table 6. where R R and R in eachcase is hydrogen and Alk in each case is (CH TABLE 6 (FORMULA 111)Example: R

83 3-CH CH OCOCH 84 4-N(n-C H 85 2-CONHCH CH=CH 86 4-N(CH2CH=CH2)3. 874-C H COO.' 88 2-(2-ClC H COOCH CH 89 4-(3-CH C H COO). 90 4-(4-HOC HCO). 91 4-(4-CH OC H COO).

92 tea-00112006113000 93 3-(4-CH SC H COO). 94 3-(4-CH SOC H COO). 953-(4-CH SO C H C00). 96 4-(4-CH CONHC H COOCH CH 97 4-[3,4-(CH O) C HCOOCH CH CH 98 4-(3-Cl-4-CH C H COOCH CH CH Example 99 2{2-[Z-(N-allylaminomethyl)-piperidyl]ethyl}indole R1, R2, and R4 are H,is (CH2)2, R5 is 2-CH NHCH CH=CH By reacting the 2-{2-[2-(N-allylcarbamyl)-1-piperidyl]-ethyl}indole prepared above in Example 85with lithium aluminum hydride in an organic solvent inert under theconditions of the reaction, for example diethyl ether or tetrahydrofuranthere can be obtained 2 {2 [Z-(N-allylaminomethyD-l-piperidyl]ethyl}indole.

Example 100 2- 2-{4-[2-(4-aminobenzoyloxy)ethyl 1 piperidyl] ethyl}indole [Ib; R R and R are H, Alk is CH CH R is 4-(4-NH C H COOCH CH H:By reacting the 2- 2-{4-['2-(4-acetylarninobenzoyloxy) ethyl 1piperidyl]ethyl} indole prepared above in Example 96 with concentratedhydrochloric acid and isolating the product from an alkaline medium,there can be obtained 2- 2- {4-[2-(4-aminobenzoyloxy)ethyl 1piperidyl]ethyl indole.

Examples 101-109 By following the manipulative procedure described abovein Example 77, substituting for the 5-chloro-2-(2- indolyl)ethyl halideused therein a molar equivalent amount of an appropriate2-(2-indolyl)ethyl halide substituted in the 1-position, there can beobtained the compounds of Formula Ib listed below in Table 7 where R andR in each case is hydrogen, R in each case is 4-HO, and Alk in each caseis CH CH TABLE 7 (FORMULA lb) Example: 2

101 CH 102 C H CH 103 4-Cl-3-CH C H CH 104 4-HOC H CH 105 3,4-(CH 0) C HCH 106 3,4-(0CH3015H3CH2).

107 4-CH SC H CH CH 108 4-CH SOC H CH CH 109 4-CH SO C H CH CH Example110 4 hydroxy-l-[fi-(3-indolyl)propionyl1piperidine [IIa; R R R and Rare H, R is 4-OH, Alk is CH CH A solution of 6.8 g. (0.05 mole) ofisobutyl chloroformate in 100 ml. of acetone was added dropwise withstirring to a solution of 9.46 g. (0.05 mole) of it-(3-indolyl)propionic acid and 5.50 g. (0.06 mole) of triethylamine in 200m1. of acetone while maintaining the temperature at about 10 to -15 C.To the mixture was then added a solution of 5.06 g. (0.05 mole) of 4-hydroxypiperidine in 210 ml. of acetone. The reaction mixture wasstirred at room temperature for about two hours, the triethylaminehydrochloride that had separated was filtered OE, and the filtrateconcentrated to dryness in vacuo. The residue was dissolved in 650 ml.of henzene and the benzene solution washed twice with water, twice witha saturated solution of sodium bicarbonate, twice again with water andfinally twice with 1 N hydrochloric acid. The solution was then dried,taken to dryness in vacuo and the residue crystallized from an ethylacetate-hexane mixture giving 7.7 g. of 4-hydroxyl-1-[B-(3-indolyl)-propionyl]piperidine, M.P. 133.0134.4 C. (corn).

Examples 111-134 4(CH2)5OH CH2CH' 4(CHg)aOH CH }Brown viscous oil.}Viseous oil.

}Dark viscous oil.

}91.492.8 C. ethyl acetate/hexane.

B-COOCHa- }107.4l08.4 C. ethyl CHzCHz acetate/hexane. Z-COOCzHs.--}86.838.4 C. ethyl CHzCHz..- acetate/hexane. 4-CONH1 203.6-205.2 C ethyl01110111..- acetate/hexane.

2 acetate/hexane. 4-OON(CzH5)z }l33.8-135.4 C. ethyl CHnCHa acetate.4-NHCOCH3 l88.8190.2 C CHzCH ethanol/hexane. 5 %1jjfi' }dark viscousoil. (when9 }Tan 011. a g g }Ye1low viscous oil. giggggg }Yellow viscousoil. 4-NHCOCH:

CH2 b l -ga e o. ethyl 4'COOCHCHwHQL- low-109:2" o.

gg%'dgfi f:":::: ethyl acetate/hexane.

CHQCH, }157.4-s.4 o. 'gg g }95.297.2 C. hexane. 3-CONHO2H CHaCHq 5}111.21l2.8 C. 4-COOCH; P2324242 C. ethyl CHZCHI acetate/hexane.

*Compound of Formula 110.

Example 135 tion of 5 .45 g. (0.02 mole) of 4hydroxy-1-[fl-(B-indolyl) 4aminocarbamyl 1 [B (3 indolyl) propionyl] piperidine [IIa; R R R and Rare H, R is 4-CONHNH Alk is CH CH A solution of 4.1 g. (0.13 mole) ofthe 4-carbomethoxy-1-[B-(3-indolyl)propionyl]piperidine, prepared abovein Example 134, in 12 ml. of 100% hydrazine hydrate and ml. of isopropylalcohol, was heated under reflux for about seven hours. The mixture wastaken to dryness in vacuo, and the resulting solid was slurried with 25m1. of saturated aqueous sodium bicarbonate solution and then filtered.The insoluble material was recrystallized from a chloroformhexanemixture giving 2.53 g. of 4-aminocarbamyl-1-[B-(3-indolyl)propionyl]piperidine, M.P. 126.9l30.4 C. (corn).

Example 136 3-[3-(4-hydroxy-1-piperidyl)propyl]indole [Ia; R R R and Rare H, R is 4-OH, Alk is (CH A solupropionyl]piperidine, prepared abovein Example 110, in 270 ml. of dry tetrahydrofuran was treated with asolution of 1.52 g. (0.04 mole) of lithium aluminum hydride in ml. ofdry tetrahydrofuran according to the manipulative procedure describedabove in Example 34. The product was isolated in the form of the freebase and recrystallized from an ethyl acetate-hexane mixture giving 2.44g. of 3-[3-(4-hydroxy-1-pipe1idyl)propyl]indole, M.P. 195.2-1982" C.(corn).

Examples 137-155 The compounds of Formulas Ia and Ic listed below inTable 9 were prepared by reducing the respective compounds of Examples111129' with lithium aluminum hydride in tetrahydrofuran according tothe manipulative procedure described above in Example 34. All meltingpoints are corrected unless noted otherwise. The compounds of Formula 10are indicated by an asterisk(*).

TABLE 9 Example Rl/Ri Bit/R4 R5/A1k Bzstsetor M.P.leryst.trom- 137{198.2201.2 C. ethyl acetate/hexane. 13s 151.s-153.2 o. ethyl acetate.139 {156.0-157.8 0. ethyl acetate/hexane. 140 {130.0-133.2 o. ethylacetate/hexane. 141 {142.0143.4 G. ethyl acetate/hexane. 142 1s2.4-1s4.e0. water.

-142.0 0. th 1 143 H e etatelhexari e. y 144 H--- do {164.2165.0 c.ethyl acetate. 145 do 160.8163.8 0. ethyl acetate. 146 do {151.4154.6 0.ethyl acetate. 147 do {1l5.6-1lfi.0 c. ethyl (CHM acetate/hexane. 148fff9jff z }2Ho1- 2454-2472" 0611131101. 149 i }2Ho1 2o2.4-20s 0.ethanol.

2772-2792" 0. 150 }2HCI"" {fimatgngl/ghanol.

1. o 151 u }HCL""{ isopropanol/ether. 152' {QOiItBiPQ C. benzene] 153 40112011--- do {85.8-87.0 c. ethyl (CH2)1 acetate/hexane. 154' H H4-CH1N(OqH )z..- }2HC1 {219.4-220.6c.1so- H E Said E1 ze h is i b-..-:1: H::::::::::: OH. -f1::t::::} proparioI/ether.

Compound Formula Ic.

Examples 156-159 TABLE 11Continued Example: R By following themanipulative procedure described 166 3gg 4 gg)- above in Example 110,substituting for the fi-(3-1nd0lyl) 241- 3191 6C4; c propionic acid andthe 4-hydroxypiperidine used therein, 1 3 6 4 molar equivalent amountsof an approprlate e-(3-1ndolyl) m caproic acid and an appropriatelower-alkylated subst1- 169 4-(3,4-0CH0 aHaCOO). tuted-piperidine, therecan be obtamed the compounds of 170 3-(4-CH SC H COO). Formula IIalisted below in Table 10 where R and R 111 171 3-(4 CH SOC H CQQ) eachcase are hydrogen and Alk in each case is (CH 172 3-(4-CH SO C H COO).

TABLE 10 (FORMULA 110) R4 Rt 11 2,4,6-triCH3- 4-HO 1 2,2,4,6,6-penta-CHa4-H0 1 fi-CgHa 2-OH:CHaOH 1 2,2-di-CHa-fi-(CH3)9CHCH1 4-H0 1 Examples160477 173 4-(4-CH CONHC H COOCH CH By following the manipulativeprocedure described 174 4- 3,4- c1-1 c 1-1 c 0cH c c1-1 above in Example110 substitutmg for the 4-hydroxy- 175 4-(3-C1-4-CH C H COOCH CH CHpiperidine used therein a molar equivalent amount of an 176 4-C H CHappropriately substituted piperidine, there can be obtained 177 4-C H CHthe compounds of Formula IIa listed below 1n Table 11 where R R R and Rin each case are hydrogen and Alk in each case is (CH TABLE 11 Example:R 160 3-CH CH OCOCH 4-N(I1-C4H9)2. 1.62 2-CONHCH CH=CH '163 4-N(CH CH=CH164 4-C H COO.

Examples 1 7 81 94 By following the manipulative procedure describedabove in Example 110, substituting for the ,8-(3-indolyl) propionic acidused therein a molar equivalent amount of an appropriate,8-(3-indolyl)propionic acid substituted i r i the land/0r 2-positions,there can be obtained the compounds of Formula IIa listed below in Table12 where R and R in each case is hydrogen, R in each case is 4-1-10, andAlk in each case is CH CH TABLE 12 (FORMULA Ila) TABLE 14 (FORMULAIIb)Continued Example: R Example R3 206 2-(2-ClC H COOCH CH 207 4-(3-CHC H COO). 5 208 4-(4=HOC H COO). 209 4(4-C-H OC H C0O).

3,4-(CH3O)2C@H=CH2 210 4-(3,4-OCH;OCH3COO).

z ggggigc egigg gm. 10 211 3 Se 1 SZ).

a B 4 2 2 21-2 3-(4-CH S c Hdp 4-CH s00 H CH CH H.i-eaisoidfifiiciizeriz. H. 213 3(4CH SO C H4OOO).

g ggg 214 4*(4 CH CONHC H C0OCH CH H Z: 4-HOC3H4. 3I1"(OH3O)2CGH=- 2164-(3Cl-4-CH C H COOCH CH CH Examples 217-225 3, -(0CH2OOsH3)- Byfollowing the manipulative procedure described i8;8 above in Example 110substituting for the fl-(3-indolyl) 4CH3sOZ 5H-ipropiomc acid usedtherein a molar equivalent amount of an appropriateB-(Z-indolyDpropionic acid substituted in Exam I6 195 the 1-position ofthe indole nucleus, there can be obtained p the compounds of Formula IIblisted below in Table 154-hydroxy-l-[a-(2-indo1y1)acetyl]piperidinc[IIb; R R Where R and R ineach case is hydrogen, R in each and R are H, Alk' is CH and R is 4-0H]:By reacting case is 4-HO, and Alk' in each case is CH CH 2-indole aceticacid with iso'butyl chloroformate and tri- TABLE 15 (FORMULA IIb)ethylamine according to the manipulative procedure de- Example: Rscribed above in Example 110 and reacting the resultlng 217 CH 2 mixedanhydride with 4-hydroxypiperidine acco g to 218 u C t; the manipulativeprocedure described above in Exa p e 219 C H CH I a 6 3 2' 110, therecan be obtained 4-hyroxy-1-[u-(2-1ndolyl)ace- 220 4 HOC6H4CH2tyl]piperidine. u

Example 196 221 3 )2 6 3 2- 4-hydroxy 1[e-(2-indolyl)hexanoyl]piperidine [IIb; R R and R are H, Alk' is c 11and R is 4-OH]: 222 MOCHZOCBHECHI- By reacting E-(2-indoly1)hexanoicacid with isobutyl chlo- 223 4-CH SC H CH CH roformate and triethylamineand reacting the resulting 224 4-CH SOC H CH CH mixed anhydride with4-hydroxypiperidine according to 225 4-CH SO C H CH CH the manipulativeprocedure described above in Example Example. 226 f? be obtamed4'hydroxy'l'[e-(z'mdolynhex'4-carbomethoxy-1-(3-indolylglyoxalyl)piperidine [IIIa; anoyllplPendme- RR R and R are H, R is 4-COOCH To a stirred Examples 197-200 solution of9.3 g. (0.04 mole) of 4-carbomethoxypiperi- By following themanipulative procedure described dine in 9 of tetrahydwful'dn Was addeddl'oPwlse above in Example 110, substituting for the a-(3-indolyl)- OverPeriod-0f aboflt f y-five mlnutes a so'lution of 1 1.3 propionic acidand the 4-hydroxypiperidine used therein (9- mole) of 3'lndolylglyoxalylchloride Whlle molar equivalent amounts of an appropriate e(2-indolyl)1a1I11I1g i p ra at When all h n ie acid and an appropriate'lower-alkylated subthe solution had been added the mixture was allowedto stituted-piperidine, there can be obtained the compounds Stand atabout 4 for twelve hQllTS- The 'mlxtul'e of Formula Ilb listed below inTable 13 where R in each wasfiltered evaporated y f 1H vacuo case ishydrogen and Alk in each case is leaving a reddish 011. The latter wastaken into chloro- TABLE 13 (FORMULA 111)) Example R1 R4 R5 n ggi' "bfif%8""""":: i eezigi'ii ff'.- -f:::::::::::::: remade-111-..- 1masons-64011920150111.. 4-HO 1 Examples 201 21 form, washed twice withdilute hydrochloric acid, three times with water, twice with saturatedsodium bicarbon- By ionowmg the mampulgtlvfa Procedure descnbed ate andthree times again with water. The chloroform P Example 9: Substltutmg fthe 4'hydroxy' solution was then dried, taken to dryness in vacuo andthe P P 'P a 9 ,eflulvalent amount of residual red viscous oil wascrystallized from an ethyl an appropriately substltuted PIPendmFi therebe 65 acetate-hexane mixture giving 10.0 g. of 4-carbomethoxytained thecompounds of Formula IIb listed below in Table 1 ,(3in.dO1y1g1yOXa1y1)piperiding p 13 Q 14, where R R and R in each case ishydrogen and (com) A-lk' in each case is CH CH Example 227 TABLE(FORMULA 3 ['2- (4-hydroXymethyl-1-piperidyl)ethyl]indole [Ia; Example:5 R R R and R are H, R is 4-CH OH, Alk is 201 3-CH CH OCOCH CH CH 2024-N(n-C H 2 203 2-CONHCH =CH By reacting the4-carbomethoxy-1-(3-indoly1gyl0xalyl)-pi- 204 4-N(CH CH=CH peridine,prepared above in Example 26 with lithium alu- 205 4C H COO. minumhydride in an organic solvent inert under the oxalyl chloride and the4-carbomethoxypiperidine used therein molar equivalent amounts of anappropriate 3- 1 indolyglyoxalyl halide and an appropnateloweraalkylated piperidine, there can be obtained the compounds ofFormula Illa listed below in Table 16 where R in each case is hydrogen.

TABLE 16 (FORMULA IIIa) Example R1 R4 R5 228 6H0 age-mom 4-HO. 229aeoorno. 2,2,4,6,6-penta-CHa 4-H0. 90 230 souls 5.0m. 201120112011. 231eouaso m 2,2-dl-CH3-6-(C 3)ICHCHQ..- 4410.

Examples 23 2-25 4 By following the manipulative procedure describedabove in Example 226, substituting for the 4-carbomethoxypiperdine usedtherein a molar equivalent amount of an appropriately substitutedpiperidine, there can be obtained the compounds of Formula IHa listedbelow in Table 17 where R R R and R in each case is hydrogen.

TABLE 17 (FORMULA IIIa) Example 255 6-benzyloxy 1[3-(4-hydroxy-1-piperidyl)propyl]indole [Ic; R is 6-C H CH O, R and Rare H, R is 4-OH, Alk is (CH By following the manipulative proceduredescribed above in Example 1, substituting for the 2-(3-indolyl)ethylbromide used therein a molar equivalent amount of a3-(6-benzyloxy-1-indolyl)-propyl halide, there can be obtained6-benzyloxy-1-[3-(4-hydroxy-1-piperidyl)propyl]indole.

Example 6 4 hydroxy-1-[;8 (6-benzyloxy-1-indolyl)propionyl]piperidine[IIc; R is 6-C H CH O, R and R are H, R is 4-OH, Alk is CH CH Byfollowing the manipulative procedure described above in Example 110,substituting for the ,B-(3-indolyl)propionic acid used therein a molarequivalent amount of B-(6 benzyloxy-1-indolyl)propionic 28 acid, therecan be obtained 4-hydroxy-1-[fl-(6-benzyloxy- 1-indolyl)propionyl]piperidine.

Example 257 4-carbomethoxy 1 (6-benzyloxy-3-indolylglyoxalyl) piperidine[IIIa; R is C H CH O, R and R are H, R is 4-COOC H By following themanipulative procedure described above in Example 226, substituting forthe 3-indolylgly-oxalyl chloride used therein a molar equivalent amountof 6-benzyloxy-3-glyoxalyl chloride, there can be obtained4-carbomethoxy-l-(6-benzyloxy-3-indo'lyglyoxalyl)piperidine.

Example 258 3-{2- [4 (3,4,5 trimethoxybenzoyloxymethyl) 1piperidyl]ethyl}-indole [Ia; R R R and R are H, R i 4-[3,4,5-(CH O) C HCOOCH Alk is CH CH A solution of 2.5 g. (0.01 mole) of the3-[2-(4-hydroxymethyl-l-piperidyl)ethylJindole, prepared above inExample 3, and 2.5 g. (0.01 mole) of 3,4,5-trimethoxybenzoyl chloride in75 ml. of acetonitrile was heated under reflux for eighteen hours. Thereaction mixture was then taken to dryness. The residue was dissolved inhot water, the solution basified with 10% aqueous sodium bicarbonatesolution, and the precipitated solid collected, dried, andrecrystallized from methanol giving 2.5 g. of 3-{ 2-[4- (3,4,5tn'methoxybenzoyloxymethyl)-1-piperidyl]ethyl} indole, M.P. 142.5-l43.4C. (corn).

Example 259 2 methyl 3-{2-[4-(Z-hydroxyethyl-l-piperidyl]ethyl} ind-olehydrochloride [Ia; R R and R are H, R is CH R is 4-CH CH OH, Alk is CHOH A mixture of 103 g. (0.8 mole) of 4-(2-hydroxyethyl)-piperidine, 193g. (1.6 mole) of 1-ch1oro-4-pentanone and 254 g. (2.4 moles) ofanhydrous sodium carbonate in 400 ml. of xylene was heated and stirredon a steam bath for twentyfour hours. The mixture was filtered to removethe precipitated inorganic salts, the filter cake was washed withabsolute ether, the washings being combined with the main filtrate, andthe filtrate evaporated to dryness. Distillation of the residual oil invacuo gave 117 g. of 1-(3- acetylpropyl) 4 (2-hydroxyethyl)piperidine,B.:P. l50 160 C./0.6 mm.; n =1.4846.

The 1 (3 acetylpropyl)-4-(2-hydroxyethyl)piperidine (10.7 g., 0.05 mole)prepared above together with 5.4 g. (0.05 mole) of phenylhydrazine weredissolved in 150 ml. of absolute ethanol containing 15.6 ml. of 6.5 Nethanolic hydrogen chloride. The mixture was refluxed and stirred fortwenty-four hours, an additional 7.8 ml. of ethanolic hydrogen chloridebeing added after the first half hour of refluxing. The mixture was thencooled, filtered, the filter cake slurrie-d with water, filtered again,and washed first with isopropanol then with n-pentane and dried to give10 g. of 2 methyl 3 {2-[4-(2-hydroxyethyl-l-piperidyl] ethyl}indolehydrochloride, M.P. 256.4-260.8 C. (corn).

Example 260 2 methyl 5,6 methylenedioxy 3-{2-[4-(2-hydroxyethyl)-1-piperidyl]-ethyl}indole hydrochloride [Ia; R is5,6-OCH O, R and R are H, R, is CH R is 4-CH CH OH,

Alk is CH CH was prepared from 9.5 g. (0.05 mole) of3,4-methylenedioxyphenylhydrazine hydrochloride and 10.7 g. (0.05 mole)of l-(3-acetylpropyl)-4-(2-hydroxyethyl) piperidine in ml. of absoluteethanol containing a total of 15.6 ml. of ethanolic hydrogen chloridefollowing the manipulative procedure described above in Example 259. Thecrude product was purified by slurrying with water, filtering andwashing the filter with isopropanol and n-pentane to give 14 g. of2-methyl-5,6- methylenedioxy 3 {2-[4- (-2-hydroxyethyl)-1-piperidyl]ethyl}indole hydrochloride, M.P. 268.8-270.0 C. (corr.).

Example 261 1 {3 [4-(5-hydroxypentyl)-1-piperidyl]propyl}indole2,3,4,5,6-pentachlorobenzochloride [10; R R and R are H, R is 4- (CH OH,Alk is (CH A mixture of 8.74 g. (0.04 mole) of 3-(-l-indolyl)propylchloride, 11.2 g. (0.05 mole) of 4-(S-hydroxypentyl)piperidinehydrochloride, and 10.0 g. (0.12 mole) of sodium bicarbonate in 300 ml.of acetonitrile was refluxed and stirred for forty-eight hours. Thereaction mixture was filtered, and the filtrate taken to dryness leaving13.9 g. of 1-{3-[4-(5- hydroxypentyl)-1-piperidyl]propyl}indole as ayellow viscous oil. I

The latter was dissolved in 325 ml. of acetonitrile along with 15.8 g.(0.05 mole) of 2,3,4,5,6-pentachlorobenzyl chloride. The mixture wasrefluxed for forty-eight hours and the solvent then taken off underreduced pressure and the residue caused to crystallize by triturationwith ether. The solid was recrystallized from isopr-opanol to give 2.2g. of 1-{3-[4 (5-hydroxypentyl)-1piperidyl] propyl}indole 2,-3,4,5,6pentachlor-obenzochloride, M.P. 183.0184.0 C. (corn).

Example 262 1 {3-[4-(3-hydroxypropyl)-1-piperidyl]propy1}indole2,3,4,5,6-pentachlorobenzochloride [Ic; R R and R are H, R is 4 (CH H,Alk is (CH was prepared from the 1 {3 [4 (3hydroxypr0pyl)-1-piperidylpropyl}indole prepared above oin Example 13and 2,3,4,5,6pentachlorobenzyl chloride in acetonitrile according to themanipulative procedure described above in Example 261. The product wasrecrystallized from isopropanol to give 1 {3[4-(3-hydroxypropyl-l-piperidyl]propyl}indo-le 2,-3,4,5,6-pentachlorobenzochloride, M.P. 159.7l63.5 C. (corn).

Example 263 3-{3-[4-(6-hydroxyhexyl) 1 piperidyl]propyl} indole2,3,4,5,6-pentachlorobenzochloride [Ia; R R R and R are H, R is 4-(CHOH, Alk is (CH was prepared from the3-{3-[4-(6-hydroxyhexyl)-1-piperidyl] propyl} indole prepared above inExample 142 and 2,3,4,5,6-pentachlorobenzyl chloride in acetonitrileaccording to the manipulative procedure described above in Example 261.The product was recrystallized from isopropanol to give3-{3-[4-(6-hydroxyhexyl)-1-piperidyl]propyl} indole2,3,4,5,6-pentachlorobenzochloride, M.P. 163.6171.2 C. (corn).

Example 264 4-cyclohexylmethyl-1-(5-fluoro 3 indolylglyoxalyl)piperidine [IIIa; R is 5-F, R R and R are H, R is 4-C H CH To a solutionof 15.22 g. (0.12 mole) of oxalyl chloride in 200 ml. of dry ether in aone liter three-necked round bottom flask equipped with a stirrer andinternal thermometer was added dropwise with stirring over a period offorty-five minutes a solution of 13.52 g. (0.1 mole) of S-fluoroindolein 250 ml. of dry ether. The mixture was stirred for one and a halfhours at O-5 C., diluted to one liter with hexane, stirred an additionalhour at C., and the yellow solid which separated was collected, washedwith hexane and dried to give 17.05 g. of 5-fluoro-3-indolylglyoxalylchloride, M.P. 160170 C. (dec., uncorr.).

The latter (0.0755 mole), dissolved in 300 ml. of dry tetrahydrofuran ina one liter three-necked round bottom flask equipped with a mechanicalstirrer and an internal thermometer, was reacted with stirring at 0-5 C.with a solution containing 18.13 g. (0.10 mole) of4-cyclohexylmethylpiperidine and 11.0 g. (0.11 mole) of triethylamine in300 ml. of dry tetrahydrofuran according to the manipulative proceduredescribed above in Example 226. The crude product, isolated according tothe procedure described above in Example 226, was recrystallized twicefrom an ethyl acetate-hexane mixture to give 23.2 g. of4-cyclohexylmethyl-1-(S-fiuoro-3-indolylglyoxa1yl)- piperidine, M.P.169.2-171.8 C. (corn).

30 Example 265 By following the manipulative procedure described abovein Example 226, substituting for the 4-carbomethoxypyperidine and the3-indolylglyoxalyl chloride used therein molar equivalent amounts of anappropriately substituted piperidine and an appropriately substitutedindolylglyoxalyl chloride, there can be obtained the compounds ofFormula IIIa listed below in Table 18 where R, in each case is hydrogen.

TABLE '18 (FORMULA I-IIa) Example R1 R3 R 266 5,6-dl-CH3O CH3--. 4CH2N(CH5) r. 267- 6-C5H5CHzO 011115.--- 4-CH7N(CH2CH=CH2): 268. G-Cl CH4-CH2N(CH3)2- 269". 6-Bl Cl-T'z 4-CH2C0H11. 270 $1-... H I-GHQCHzOH.

The compounds of Formulas Ia, b, and c have been shown to possesshypotensive, sedative, anti-inflammatory, monoamine oxidase inhibitory,coronary dilator, adrenolytic, tranquilizing, and anti-bacterialactivities. As representative of these various activities shown by thecompounds of the invention are the following:

The minimum effective hypotensive dose (MEHD) of 3-[2-(4-hydroxy-1-piperidyl)ethyl] indole, prepared above in Example 1,administered subcutaneously in the renal hypertensive rat, was found tobe about 1.0 mg./kg.; the MEHD of 3-[2-(2-hydroxymethyl 1piperidyl)ethyl] indole, prepared above in Example 4, administeredintravenously in the anesthetized dog, was found to be 1.0 mg./kg.; andthe MEHD of 3-[2-(4-isopropylidenehydrazono-l-piperidyl)ethyl]indole,prepared above in Example 31, administered subcutaneously in the renalhypertensive rat, was found to be about 1.0 mg./kg.;

Sedative activity was determined by the potentiation of hexobarbitalinduced sleeping time in mice. Thus the effective dose, ED of3-{2-[4-(1-hydroxyethyl)-1- piperidyl]ethyl}indole hydrochloride,prepared above in Example 6, in inducing sleep in mice to which 40 mg./kg. of hexobarbital had been administered was found to be 106:465mg./kg. (oral);

3-[3-(4-hydroxymethyl-l-piperidyl)propyl]indole, prepared above inExample 138, and 1-[3-(2,6-dimethyl-4- hydroxy-l-piperidyl)propylJindolehydrochloride, prepared above in Example 151, were found to haveantiinflammatory activity as evidenced by inhibition of dextran edema inrats when administered orally at a dose level of mg./kg./ day for threedays;

3-[2-(4-isopropylidenehydrazono 1 piperidyl)ethyl] indole, preparedabove in Example 31, 1-[3-(4-hydroxymethyl-l-piperidyl)propylJindole,prepared above in Example 153, and 3-[2-(4-amino-carbamyl-l-piperidyl)ethyl]indole, prepared above in Example 30, were found to be aboutone-tenth as active as iproniazid as a monoamine oxidase inhibitingagent;

3-{3-[4-(3 hydroxypropyl)-1-piperidyl] propyl}indole, prepared above inExample 139, was found to produce 7.8% coronary dilatation at a doselevel of 0.1 mg./kg. in the isolated rabbit heart;

3-{3-[4-(6-hydroxyhexyl) 1 piperidyl]propyl}indole hydrochloride,prepared above in Example 142, administered intravenously in rats,showed adrenolytic activity as evidenced by antagonism of the pressoreffects of epinephrine. The effective dose, ED in antagonizingepinephrine was found to be 73012161 mcg./kg.;

3-{2-[4-( l-hydroxyethyl)-1-piperidyl]ethyl}indole hydrochloride,prepared above in Example 6, administered orally producedtranquilization of mice as evidenced by the reaction of the mice tobeing touched lightly on the vibrissae. The effective dose, ED inproducing tranquilization in mice was found to be about 128 mg./kg.;

In standard serial dilution tests, 3-[3-(2,6-dimethyl-4-hydroxy-1-piperidyl)propyl]indole, prepared above in Example 137, wasfound to be bacteriostatically elfective at a dilution of 122,000 vs.Staph. aureus and Cl. welcheii, and about 121,000 vs. E. 'typhi and Pr.aeruginosa.

The compounds of Formulas Ila, b, and 0 have been shown to possesshypotensive and coronary dilator activities. compounds are thefollowing:

The MEHD of 4-aminocarbamyl-1-[fi-(3-indolyl) propionylJpiperidine,prepared above in Example 135, administered subcutaneously in the renalhypertensive rat was found to be 1.0 mg./kg.;

4-acetylamino-1-[13 (3 indoly1)propionyl]piperidine, prepared above inExample 124, 4(N,N-diethylcarbamyl) 1[fi(3-indolyl)propionyl]piperidine, prepared above in Example 123, and4-carbomethoxy-1-[B-(3- indolyl)propionyl]piperidine, prepared above inExample 134, were found to produce 1.6%, 3.1%, and 2.4% coronarydilatation, respectively, at a dose level of 0.1 mg./kg. in the isolatedrabbit heart.

I claim:

1. A compound having the formula where R is from one to two membersof-the group As representative of these activities shown by theconsisting of hydrogen, hydroxy, halogen, lower-alkoxy, methylenedioxy,lower-alkylmercapto, lower-alkylsulfonyl, and benzyloxy; R is a memberof the group consisting of hydrogen, lower-alkyl, and monocarbocyclicaryl; R is a member of the group consisting of hydrogen and from one tofive lower-alkyls; and R is a member of the group consisting of hydroxy,hydroxy-lower-alkyl, lower-alkanoyloxy, monocarbocyclic aroyloxy,loweralkanoyloxy-lower-alkyl, monocarbocyclic aroyloxylower-alkyl,cycloalkyl-lower-alkyl, carbo-lower-alkoxy, unsubstituted-carbamyl,N-lower-alkylcarbamyl, N-loweralkenylcarbamyl,N,N-di-lower-alkylcarbamyl, N,N-dilower-alkenylcarbamyl,N,N-di-lower-alkylaminomethyl, N,N-di-lower-alkenylaminomethyl,N,N-di-lower-alkylamino, and N,N-di-lower-alkenylamino; and n is theintegers 1 and 2.

2. A compound having the formula COCON S 2 wherein R iscarbo-lower-alkoxy.

3. A compound having the formula COCON 2 R1 R5 wherein R is halogen andR is cycloalkyl-lower-alkyl.

4. 4-carbomethoxy-1-(S-indolylglyoxalyl)piperidine. 5. 4cyclohexylmethyl-1-(5-fluoro-3-indolylglyoxalyl)- piperidine.

References Cited by the Examiner Speeter et al., I. Am. Chem. Soc., vol.76, pages 6208-10.

NICHOLAS S. RIZZO, Primary Examiner.

1. A COMPOUND HAVING THE FORMULA